The present invention relates to the field of emulsion compositions and to pharmaceutical dosage forms and the methods of preparing the same.
Certain drugs present significant problems in balancing the desire for a convenient oral dosing format and the necessary bioavailability. With some drugs, absorption of an orally administered dose could be as little as 30%, or less. Such poorly absorbed drugs often display large inter- and intra-subject variability in bioavailability. See Aungst, B. J., J. Pharm. Sci., 82:979-987, 1993. Specific examples of such drugs, having the average bioavailability given in parentheses, include methyldopa (25%) with a range of 8% to 62%; and nalbuphine (approximately 17%) with a range of 6% to 40%.
The absorption rate of most drugs depends on two factors: (1) the dissolution of the drug in physiological fluids and (2) the absorption process itself, i.e., the process by which a drug in solution enters the cells at the absorption site and, finally enters the general circulation. Many drugs are absorbed by passive diffusion, i.e., a spontaneous migration of drug molecules from a region of high concentration to a region of low concentration. Other drugs are absorbed by active transportation which involves the expenditure of energy by the body. Some drugs are absorbed by the processes of pynocytosis or endocytosis which involve the engulfing of solid particles and the incorporation of such particles into the cellular contents. However, with these few exceptions, for solid orally administered drugs, absorbed actively or passively, dissolution of the drug is the first step in the absorption process.
To compensate for the poor absorption displayed by many drugs, a pharmaceutical formulation may utilize or take advantage of one or more mechanisms to increase the rate and/or the extent to which the administered drug is absorbed. While there are a vast number of such mechanisms, they may be grouped into the following broad categories: (1) techniques that increase rate of absorption by enhancing the rate or extent of dissolution; (2) techniques that increase rate of absorption by facilitating the absorption process that would have occurred naturally; and (3) techniques that increase rate of absorption by inducing an absorption mechanism that would not naturally have occurred or which would have occurred to an insignificant extent in the absence of any special absorption-enhancing mechanism. Incorporation of surfactants to increase the rate of dissolution of a slowly-dissolving drug is an example of a technique which takes advantage of the first mechanism, and incorporation of a chemical substance that opens tight junctions in order to increase the rate of absorption of a drug that would normally have been absorbed slowly through the paracellular route is an example of the use of the second technique. On the other hand, incorporation of a drug within oil droplets for the purpose of using the lymphatic system in the absorption of the drug (where this would not, otherwise, have occurred) is an example of a third technique using the third mechanism.
Emulsions have also been used for delivering drugs. The emulsions are generally delivered only in the form of soft or hard gelatin capsules, or as a liquid dispensed directly into the patient""s mouth. However, gelatin capsule shells contain water which can migrate into water-in-oil (xe2x80x9cw/oxe2x80x9d) emulsions. This can change the relative proportions of the different phases of the emulsion and/or cause the gelatin shell to become dry and susceptible to cracking. Alternatively, a w/o emulsion can lose water to the gelatin shell, again changing the proportions of the different emulsion phases or causing the shell to swell and become soft. The latter effect makes it difficult for a patient or care-giver to handle the capsule. Moreover, surfactants and co-surfactants within the emulsions, often used as emulsifying agents, can react with the capsule shell. Oil-in-water (xe2x80x9co/wxe2x80x9d) emulsions generally cannot be incorporated in such capsules because the water in the external phase will dissolve the capsule shell. In addition, gelatin capsules which contain liquids present handling problems to both the patient and the manufacturers. Capsule leakage is a common problem and sophisticated detection systems are sometimes employed to monitor such leakage. Upon physical handling by the patient, the capsule may also soften or leak. With prolonged storage at temperatures and humidity levels that are not as closely controlled as the environment in a pharmaceutical factory, the capsule may also swell, shrink or leak.
More recently, powdered solution technology has been proposed as a technique for the delivery of water-insoluble drugs. See Spireas et al., xe2x80x9cPowdered Solution Technology: Principles and Mechanisms, Pharm. Research, Vol. 9, No. 10 (1992) and Sheth, A. and Jarowski, C. I., xe2x80x9cUse Of Powdered Solutions To Improve The Dissolution Rate Of Polythiazide Tablets,xe2x80x9d Drug Development and Industrial Pharmacy, 16(5), 769-777 (1990). The concept of powdered solutions involves converting drug solutions or liquid drugs into a dry, nonadherent, free-flowing compressible powder by admixing the liquid drugs or drug solutions with a selected carrier. Although the dosage form is a solid, the drug is held in a solubilized liquid state, which enhances diffusion directly into cells. Alternately, it improves the wetting properties of the drug and, therefore, enhances dissolution.
Unfortunately, the application of powder solution technology has been limited.
While the technology offers certain promise in enhancing the drug-delivery performance, in practice, the resulting admixture powders generally have undesirable properties, such as poor and erratic flowability and compressibility. The disclosure of the co-pending commonly assigned U.S. patent application Ser. No. 09/374,393 and the corresponding international application PCT/US99/18552 published under Pub. No. WO009093A1 is incorporated herein by reference.
One aspect of the invention provides an emulsion composition in the form of a free-flowing, compressible powder, which includes an admixture of a drug-containing emulsion and a solid particle adsorbent; wherein the emulsion is adsorbed on the solid particle adsorbent and forms a free-flowing, compressible powder. The drug-containing emulsion remains stable in the composition. Preferably, the drug containing emulsion has a viscosity of between 1 cps and 400,000 cps, preferably between 400 cps and 200,000 cps and more preferably between 5,000 cps and 150,000 cps. The drug-containing emulsion may include between 2% and 50% active drug ingredient, preferably between 5% and 40% and more preferably between 10% and 30%.
The emulsion compositions according to this aspect of the present invention do not limit the types of dosage form and can be administered to a subject in any pharmaceutically acceptable dosage. For example, the emulsion compositions may be administered as dosage forms, such as tablets; granules, pellets or other multiparticulates; capsules that can contain the drug in the form of mini-tablets, beads, or a powder; suppositories; or as a powder of the emulsion composition itself, either packaged in a multidose container or as individual doses.
In another aspect, the invention also provides an emulsion composition in the form of a free-flowing, compressible powder. The emulsion composition is an admixture of a drug-containing self-emulsifying drug delivery system and solid particle adsorbents. The drug-containing self-emulsifying drug delivery system is a mixture of oil, emulsifying agent and active drug ingredient and the mixture is adsorbed onto the solid particle adsorbent when blended with the adsorbent. Compositions according to this aspect of the invention can be made into dosage forms similar to those discussed above.
The emulsion compositions discussed above may be prepared by adsorbing a drug-containing emulsion onto a particulate solid material so as to provide the emulsion composition in the form of a powder. The powder can then be made into other solid dosage forms by combination with additional excipients using conventional processing. The dosage form of the emulsion composition can also be directly packaged and administered without further processing.
Administration of drugs in the above-mentioned dosage forms offers significant advantages over the previously available methods of administration.
In certain preferred embodiments of the present invention, absorption of the drug is facilitated by the administration of the drug-containing-emulsion compositions. Although the present invention is not limited by any theories of operation, it is believed that upon the disintegration of a dosage form which contains the emulsion compositions of the invention, emulsion droplets are distributed through a large volume of the gastrointestinal fluids. This prevents the formation of large agglomerates of individual emulsion droplets in localized regions. When the droplets come into contact with the surface tissues of the body cavity, this widespread distribution aids in the absorption of the drug over a large surface area.
In another aspect of the invention, emulsion compositions and dosage forms containing them are used to enhance the bioavailability of poorly absorbed drugs that are oil soluble. This is accomplished by administering these drugs as oil-in-water (o/w) emulsions. The oil soluble drug is distributed as droplets of an oily solution which is then used to make an emulsion where water is the continuous phase. The emulsion is adsorbed onto a powder and formulated into a dosage form. When ingested, oil droplets may be absorbed by the tissue together with the incorporated drugs. The oil droplets may also be positioned adjacent to the absorbing surface so that the drug in such oil droplets can diffuse into the cell membrane. In addition, due to the fact that there are many such droplets, as noted above, the surface area of the absorbing tissues with which the droplets make contact is large, thus facilitating absorption. Furthermore, since in vivo agglomeration is retarded, absorption can be facilitated.
The emulsion compositions of the present invention may be also used to promote absorption though the M-cells of Peyer""s patches. These M-cells are involved in the absorption of very small solid particles of the order of 10 micrometers. Since the individual solid support particles described in this disclosure only partially release the emulsion droplets following administration of the dosage forms to mammals, there are free emulsion droplets as well as emulsion droplets attached to solid particles at the absorption site. In a preferred embodiment, the droplet-solid support complex is sufficiently small to be absorbed via the M-cells.
The emulsion globules of the emulsion compositions of the invention may also promote absorption though the lymphatic system. Such absorption relates especially to the free (detached) emulsion droplets but may also relate to the droplets adsorbed and remain adsorbed onto the carrier support. Drugs absorbed via the lymphatic system pass directly from this system into the general blood circulation and hence avoid the first pass effect.
In addition, emulsion compositions in accordance with the invention may facilitate administration of drugs that are subject to metabolic breakdown or degradation in the gastrointestinal tract, such as, for example, peptides, proteins, oilgonucleotides and other biological molecules. Such drugs may be protected within, for example, the oil droplets in o/w emulsions. As used herein, the word xe2x80x9cprotectionxe2x80x9d refers to the protective effect that reduces the rate and/or extent of the drug molecule degradation in vivo. The emulsion components of the present invention make it difficult for enzymes and other chemical substances to react with such drug molecules when they are encased in oil and/or the emulsifying agent(s).
The emulsions of the present invention are administered in the form of solid particles which may be further formulated into solid dosage forms. The drug-containing emulsions are adsorbed onto a solid particulate (i.e., powder). Although the drug is in a solid form, it is maintained as an emulsion, or in the case of self-emulsifying drug delivery systems (xe2x80x9cSEDDSxe2x80x9d), in a state readily converted to an emulsion in vivo. Preferably, these formulations enhance dissolution into aqueous fluids and/or absorption into the body. Although the present invention is not limited by any theories of operation, it is believed that the SEDDS is adsorbed on the adsorbent particles in the form of oil globules or form a film. When these SEDDS-containing adsorbent particles are administered and in contact with the body fluid, they form an emulsion composition.
SEDDS consists of all components of the emulsion except the water i.e. it consists of the oil phase, emulsifying agents, anti-oxidants, preservatives and other optional excipients. Upon mixing with the stomach contents, an emulsion is formed. It can be distinguished from an emulsion in that it is a one-phase system: it does not have droplets of one liquid distributed throughout a second liquid. It can be distinguished from an oil (that may be adsorbed on a solid support) by the fact that the oil does not contain emulsifying agents and, in general, will not form an emulsion upon mixing with the stomach contents.
In addition to enhancing the saturation concentration (saturation solubility) of the pharmaceutical substance, the pharmaceutical compositions and solid dosage forms of the present invention also increase the substance surface area of the drug-containing emulsion. The adsorbent particles increase the area available for interaction with gastrointestinal fluids and/or with the site of absorption to thereby promote absorption of the drug.
In a further preferred aspect of the present invention, an emulsion composition is in a solid dosage form that is convenient and easy to handle. The solid dosage forms represent a robust, stable dosage form. Moreover, the solid dosage form that is more patient-acceptable and thus provides potential for better patient compliance. There are many patients who do not like to take capsules and for whom an alternate dosage form, such as a tablet, is preferable. In addition, the present invention provides a form for the oral administration of peptides which are generally administered by injection, which is unpleasant for the patient.